Off Target On Off-Label Drugs

Americans are becoming increasingly dissatisfied with their government, according to opinion polls released in April by the Pew Research Center. The center's president, Andrew Kohut, said, "Rather than an activist government to deal with the nation's top problems, these surveys show that the general public now wants government reformed and a growing number want its power curtailed. With the exception of greater regulation of Wall Street, there is less of an appetite for government solutions to the nation's problems--including greater government control over the economy--than there was when Barack Obama first took office."

What is particularly stunning about these findings is that public sentiment is so strong while many people are unaware of important information. Consider, for example, a common aspect of U.S. medical care: doctors’ prescribing medicines "off-label"--that is, the use of approved medicines for purposes not yet sanctioned by the Food and Drug Administration (FDA).

Before a drug can be sold in the U.S., it must be certified by the FDA as safe and effective for a specific, or "on-label," use; but traditionally, once it has been approved, physicians may legally prescribe it for any other purpose. On the basis of articles in medical journals and information gleaned from conferences, doctors prescribe this way more than 100 million times a year. By some estimates, at least 20% of all prescriptions written are off-label, and those uses often constitute the accepted standard of care. The practice is ubiquitous in cancer and cardiac treatment, where as many as half of all prescriptions are for off-label uses. In the absence of off-label prescribing, physicians would have fewer treatment options and many patients would die or suffer needlessly.

Off-label prescribing is controversial with regulators and some politicians, who view it as a way to shortcut clinical testing and skirt the FDA approval process. But the American Medical Association is convinced that "physicians have the training and experience to determine the best or preferred method of treatment," and that off-label prescribing should often be considered "reasonable and necessary medical care, irrespective of labeling." In fact, doctors can be subject to malpractice liability if they do not use drugs for off-label indications when doing so constitutes the standard of care.

And at least in theory, even the FDA acknowledges that off-label prescriptions are sometimes necessary for the practice of good medicine. According to the agency's website, "Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects."

But decades of actions by regulators belie that temperate language. The FDA, with support from many in Congress, has sought repeatedly to limit physicians' and patients' discretion about treatment decisions, including restricting physicians from prescribing drugs off-label and interfering with drug companies' ability to disseminate information about new uses of approved drugs. Arguably, instead of such intransigence, the FDA should maintain a database of information about off-label uses of drugs. That would make life easier for physicians and safer for patients.

Two fairly recent developments illustrate what a quagmire the off-label use of drugs has become.

The first is the Food and Drug Administration Amendments Act (FDAAA), which took effect on March 25, 2008, and gave the FDA sweeping new powers. One of these is the ability to require a Risk Evaluation and Mitigation Strategy (REMS) for any newly approved drug. According to the FDA, a REMS is "a strategy to manage a known or potential [sic] serious risk associated with a drug or biological product," which could be said to encompass virtually any medicine.

The agency's explanation continues, "A REMS can include a Medication Guide, Patient Package Insert, a communication plan, elements to assure safe use, and an implementation system, and must include a timetable for assessment of the REMS." The term "elements to assure safe use" sounds benign enough but regulators' demands can be so drastically restrictive as to constitute a new, distinct and limited, or conditional, class of approvals--one that makes off-label prescribing much more cumbersome and difficult.

The elements to assure safe use as defined in the FDAAA may include a requirement that:

--"Health care providers who prescribe the drug have particular training or experience, or are specially certified."

--"Pharmacies, practitioners or health care settings that dispense the drug are specially certified."

--"The drug is dispensed to patients only in certain health care settings, such as hospitals."

--"The drug is dispensed [only] to patients with evidence or other documentation of safe use conditions, such as laboratory test results."

--"Each patient using the drug is subject to certain monitoring."

--"Each patient using the drug is enrolled in a registry."

All of these conspire to reduce physicians' off-label prescribing. Just as important an impediment, however, is an FDA policy that restricts what drug manufacturers may say about off-label uses. The agency uses its authority over drug labeling and "promotion" (which regulators construe to encompass not just advertising but virtually any contact with health professionals or patients) to prevent manufacturers from disseminating information about off-label uses, even to doctors. Drug firms may send peer-reviewed medical journal articles and excerpts from medical textbooks to physicians and, in some circumstances, they are permitted to answer questions asked directly by physicians, but almost everything else is forbidden.

These FDA policies compromise physicians' ability to learn about and use new pharmaceuticals. A series of national surveys commissioned by the Competitive Enterprise Institute has shown that a large majority of physician specialists--including oncologists, cardiologists, emergency room doctors, orthopedic surgeons and neurologists--believe the FDA's policies have made it more difficult for them to learn about new uses for drugs and medical devices, and that the agency should not restrict information about off-label use.

Although the FDA's REMS authority has made it more difficult for physicians to prescribe off-label, another development might have the opposite effect.

In October 2009 California-based drug manufacturer Allergan filed a lawsuit against the FDA arguing that the near-total ban on the distribution of truthful information about safe and effective off-label uses of medicines is not authorized by the Federal Food, Drug and Cosmetics Act, and that even if it were, the ban would be an unconstitutional abridgment of commercial free speech. The federal District Court for the District of Columbia will hear oral arguments from the parties later this year. It could be years before the case is finally resolved, but an Allergan victory would be a huge boon for millions of American patients.

The suit revolves around a REMS requirement for Allergan's drug Botox, which has been approved for treating muscle spasms in the neck and eyes, as well as for its hugely popular cosmetic purposes. But it is widely used off-label as well to treat various other kinds of muscle spasticity and also speech impediments and migraine headaches.

Last September, using its REMS authority, the FDA ordered Allergan to send detailed safety updates to physicians who prescribe Botox for both on-label and off-label indications. The company felt that regulators had placed it in a Catch-22 situation: Complying fully with the order could violate the FDA ban on promoting drugs for off-label uses.

The FDA and federal prosecutors take these restrictions very seriously, charging violators with both civil and criminal sanctions. In 2009 drug manufacturer Pfizer pleaded guilty to criminal charges and paid a record $2.3 billion to settle allegations of promoting 14 of its products for off-label uses, and Eli Lilly was forced to pay $1.4 billion for promoting its schizophrenia drug Zyprexa for off-label use. On April 27, 2010, the Department of Justice announced a $520 million settlement with pharmaceutical manufacturer AstraZeneca that resolved allegations that the drug maker had illegally promoted off-label uses of the company's antipsychotic drug Seroquel.

It appears that no possible violation is too minor to attract regulators' attention. Earlier this year the FDA even sent a warning letter to a Florida dermatologist for mentioning in interviews with Elle and Allure magazines and on NBC's Today show that an anti-wrinkle drug she was testing had shown positive results and that "early data shows it may last longer and kick in faster than Botox."

It is easy to see, then, why Allergan was hesitant to comply with the FDA's order. Providing information to doctors about patient selection, dosage and appropriate injection sites for off-label uses could subject Allergan to huge fines and threaten the company and its employees with criminal penalties.

The FDA's policies raise serious constitutional questions. Prior to 1999 FDA regulations prohibited even the distribution of peer-reviewed medical studies unless the manufacturer had already submitted to the agency a supplemental application for approval of the off-label use in question. The nonprofit Washington Legal Foundation challenged those rules, however, and a federal district court held that the near-blanket ban on disseminating truthful and non-misleading information about off-label uses was an unconstitutional restriction of commercial speech. The FDA only avoided having its regulations totally invalidated when agency lawyers claimed that the rules merely established a "safe harbor" under which manufacturers would be automatically deemed in compliance with the law, but that the regulations did not really prevent all off-label promotion.

Having been reprimanded by the court, the FDA eventually conceded that drug and device manufacturers do have some First Amendment rights. In 2009 the agency issued a guidance document that acknowledged explicitly that drug and device firms may sometimes distribute medical journal articles and text book excerpts to physicians. The guidance also suggested indirectly that other actions might be lawful, but aside from the journal and textbook exemptions, the FDA won't tell anyone what is and is not permitted. And in practice the agency refuses to permit distribution of any other kinds of information about off-label uses.

That is surely why Allergan felt it had no other choice but to seek clarification from the courts. The company acknowledges that the FDA may forbid false or misleading claims but has petitioned the court to hold unconstitutional the FDA's near total ban on truthful and non-misleading information. A key precedent may be a landmark 2002 case involving advertising by pharmacists in which the U.S. Supreme Court concluded that the "First Amendment directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good."

Perhaps via the judiciary, society must balance safety with the right of patients and their physicians to make decisions about medical therapies.